Finding keys to drug therapy resistance in glioblastoma

Researchers have found one of the keys to why certain glioblastomas, the primary form of a deadly brain cancer, are resistant to drug therapy. The answer lies not in the DNA sequence of the tumor, but in its epigenetic signature.

"There is a growing interest to guide cancer therapy by sequencing the DNA of the cancer cell," said Clark Chen, MD, PhD, vice-chairman of Research and Academic Development, University of California (UC), San Diego School of Medicine, Division of Neurosurgery, and the principal investigator of the study, published in Oncotarget (2014;5[6]:1515-1525). "Our study demonstrates that the sensitivity of glioblastoma to a drug is influenced not only by the content of its DNA sequences, but also by how the DNA sequences are organized and interpreted by the cell."

The team of scientists, led by Chen, used a method called comparative gene signature analysis to study the genetic profiles of tumor specimens collected from approximately 900 glioblastoma patients. The method allows investigators to discriminate whether specific cellular processes are turned on or turned off in glioblastomas.

"Our study showed that not all glioblastomas are the same. We were able to classify glioblastomas based on the type of cellular processes that the cancer cells used to drive tumor growth," said co-first author Jie Li, PhD, senior postdoctoral researcher in the Center for Theoretical and Applied Neuro-Oncology at UC San Diego.

One of these cellular processes involves epidermal growth factor receptor (EGFR). The study revealed that EGFR signaling is suppressed in a subset of glioblastomas. Importantly, this suppression is not the result of altered DNA sequences or mutations. Instead, EGFR is turned off as a result of how the DNA encoding the EGFR gene is organized in the cancer cell. This form of regulation is termed epigenetic. Because EGFR is turned off in these glioblastomas, they become insensitive to drugs designed to inhibit EGFR signaling.

"Our research suggests that the selection of appropriate therapies for our brain tumor patients will require a meaningful synthesis of genetic and epigenetic information derived from the cancer cell," said co-first author Zachary J. Taich.